CCRP Multiple Myeloma

Summary

The Heidelberg Myeloma Program is internationally renowned for the diagnosis and treatment of patients with monoclonal plasma cell diseases. In 2016 more than 7500 outpatient contacts, about 360 new patient admissions and 197 autologous hematopoietic stem cell transplantations were coordinated and supervised by the “Section Multiple Myeloma” of the Department of Hematology and Oncology, University Hospital Heidelberg and National Center for Tumor Diseases (NCT) Heidelberg.

The German-speaking Myeloma Multicenter Group (GMMG) headed by Hartmut Goldschmidt is the largest study group focusing on MM in Germany. Its Headquarter is based in Heidelberg. Within the last 20 years, the GMMG study group has performed numerous trials including five randomized, multicenter Phase III clinical trials with about 3000 patients enrolled from 74 centers throughout Germany, Austria and Switzerland.Translational research projects of the group focus on systems medicine using “omics”- and imaging data in clinical routine and their integration with conventional clinical data in personalizing myeloma treatment. Overall goal of the Heidelberg Myeloma group is to generate improved therapies for myeloma patients through the development and testing of novel and personalized, genome- and signaling-driven treatment strategies.

Generating improved therapies for relapsed and refractory multiple myeloma patients through the development and testing of novel personalized, genome- and signaling-driven treatment strategies.

Systems medicine: prediction of survival, response to treatment or therapy-limiting side effects and assessment of targets by interrelation between different “omics”, molecular and conventional clinical and imaging data. Development of prognostic markers to define and monitor high-risk smoldering myeloma.

Improving results of high-dose therapy followed by autologous hematopoietic stem cell transplantation and including new compounds in myeloma treatment.

Clinical Aims

To further improve the comprehensive patient care for Myeloma patients in terms of quality of life and overall survival.

Enrollment of many patients in innovative diagnostic and treatment programs / trials for both newly diagnosed and relapsed / refractory multiple myeloma patients.

Cure of Multiple Myeloma

Systems medicine by combining and integrating GEP-, RNA-sequencing- and GWAS data with conventional clinical, imaging and molecular data (e.g. iFISH) to provide a more complete characterization of the individual patient.

The Heidelberg Multiple Myeloma Section was founded in 2005 and is shared between the Heidelberg University Hospital and National Center for Tumor diseases (NCT) Heidelberg.

Within a Germany-wide network, the German-Speaking Myeloma Multicentre Group (GMMG) headed by Hartmut Goldschmidt carries out phase III clinical studies improving high dose therapy as well as phase I/II clinical trials evaluating new compounds for multiple myeloma treatment. The results of the GMMG- trials are continuously changing standards of myeloma treatment. Results of the study group contributed to a change of the standard induction treatment in Germany (to a Bortezomib based induction).

The adverse impact of deletion (17p13) on PFS and OS of Myeloma patients could be significantly reduced by Bortezomib based treatment (Neben et al. Blood 2012) and Bortezomib treatment of Multiple Myeloma patients during induction and maintenance improves complete response and achieves superior PFS und OS (Sonneveld et al. J Clin Oncol. 2012). The GMMG study group further investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial. In conclusion, compared to IV bortezomib, SC bortezomib in PAd and VCD induction therapy reduced toxicity and achieved similar overall response rates, regardless of whether adverse prognostic factors such as ISS stage III disease, renal impairment or cytogenetic abnormalities were present at initial diagnosis (Merz et al. Haematologica 2015). The GMMG-MM5 trial also demonstrated non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/ dexamethasone (PAd) induction therapy with respect to response. Despite higher rates of leukocytopenia/neutropenia, which did not translate into increased infection rates, VCD has a favorable toxicity profile in terms of the total numbers of SAEs during IT, neuropathy rates and thromboembolic events. VCD is therefore an established standard IT in newly diagnosed transplanteligible MM and is recommended to be preferred over Pad (Mai et al. Leukemia 2015).

When using targeted biomarker based therapies in a patient with refractory myeloma the development of resistance can be overcome or even prevented. We showed for the first time that combining of compounds with complementary mechanisms of action is very successful. This represents a significant step toward the goal of personalizing treatment for this genetically complex malignancy (Raab et al. Blood 2016).

Imaging methods like whole-body MRI serve as an excellent tool to non-invasively display bone marrow infiltration patterns, especially in patients with early stages of monoclonal plasma cell disease. The presence of focal lesions detected by whole-body MRI in a well-documented group of individuals with MGUS is prognostically significant (Hillengaß et al. Leukemia 2013).

Targeted sequencing of refractory myeloma revealed a high incidence of mutations in CRBN and Ras pathway genes. In a cohort of 50 heavily pretreated refractory myeloma patients 88 frequently mutated or drug resistance pathway myeloma genes with a focus on genes relevant to IMiD and PI interactions were investigated. Compared with newly diagnosed myeloma, an increased prevalence of mutations in the Ras pathway genes, as well as TP53, CRNB and CRBN pathway genes was observed. These data indicate a differential genetic landscape in refractory myeloma associated with drug response. (Kortüm et al. Blood 2016).

Together with other groups we identified genetic risk factors for Multiple Myeloma by developing the largest Genome wide association studies (GWAS) of Multiple Myeloma to date. We identified eight novel MM risk loci taking the total count to 17. Our findings provide further evidence for an inherited genetic susceptibility to MM and provide the first steps in identifying the genetic causes of Myeloma. (Chubb et al. Nat Genet. 2013, Mitchell et al. Nat. Commun. 2016).